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(Circulation. 2001;104:1805.)
© 2001 American Heart Association, Inc.

Clinical Investigation and Reports

Vasoconstrictor Effect of the Angiotensin-Converting Enzyme–Resistant, Chymase-Specific Substrate [Pro¹¹_D-Ala¹²] Angiotensin I in Human Dorsal Hand Veins

In Vivo Demonstration of Non-ACE Production of Angiotensin II in Humans

John E. McDonald, BSc MB, ChB, MRCP; Neal Padmanabhan, MA BM, BCh, MRCP; Mark C. Petrie, BSc MB, ChB, MRCP; Chris Hillier, BSc PhD; John M.C. Connell, MD FRCP; John J.V. McMurray, MD FRCP, FESC

From CRI in Heart Failure (J.E.M., M.C.P., J.J.V.M.) and Department of Medicine and Therapeutics (N.P., J.M.C.C.), University of Glasgow, and Vascular Assessment Group, Department of Biological and Biomedical Sciences, Caledonian University (C.H.), Glasgow, Scotland, UK.

Correspondence to Professor John J.V. McMurray, CRI in Heart Failure, Wolfson Building, University of Glasgow, Glasgow, Scotland, United Kingdom, G12 8QQ. E-mail j.mcmurray{at}bio.gla.ac.uk

Background— [Pro¹¹_D-Ala¹²] angiotensin I is an ACE-resistant substrate specific for chymase. We used this peptide to determine whether a functionally significant non-ACE angiotensin (Ang) II–generating pathway exists in human dorsal hand veins.

Methods and Results— Using a modified Aellig technique, we studied the response to Ang I and [Pro¹¹_D-Ala¹²] Ang I in dorsal hand veins in vivo in patients with coronary heart disease. We measured the venoconstrictor effect of each peptide given before and after a 6.25-mg oral dose of the ACE inhibitor captopril or matching placebo. Placebo or captopril was given in a double-blind, randomized fashion. Ang I induced a mean±SEM venoconstrictor response of 45±11%, 40±10%, 55±8%, and 4±4% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, the response to Ang I was reproducible and was reduced significantly only after treatment with captopril (P=0.002). [Pro¹¹_D-Ala¹²] Ang I induced a mean venoconstrictor response of 42±9%, 49±9%, 48±10%, and 54±11% before placebo, after placebo, before captopril, and after captopril, respectively. Hence, captopril had no significant effect on the response to [Pro¹¹_D-Ala¹²] Ang I.

Conclusions— We have demonstrated that [Pro¹¹_D-Ala¹²] Ang I is able to induce venoconstriction in humans in vivo. With this specific pharmacological probe, we have shown that a non-ACE pathway capable of generating Ang II exists in human veins in vivo and is potentially functionally important. This pathway is likely to involve the enzyme chymase.

Key Words: angiotensin • peptides • veins • vasoconstriction • enzymes

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